Top 10 pipeline blowups, set­backs and sna­fus in H1 2017

As Big Pharma and the growing biotech sector shifted their R&D sights over the past decade — focusing more on game-changing drugs and shunning the me-too variety that don’t fare well with payers — the usual pitfalls, setbacks and snafus have grown more spectacular with each passing year. You have to break it down into 6-month allotments just to keep a handle on the consequences of major breakdowns.

This list, though, also raises questions about the role the FDA has come play in raising risks for patients in cancer studies. Two of my 10 drugs on the hit list are oncology drugs that were put on hold — briefly — only to get yanked again after more deaths hit the drug arm of the pivotal study. Is the FDA doing its job properly in evaluating the risks associated with experimental cancer drugs? Or has the rush to get new approvals caused regulators to lower safety standards too far?

The FDA has received considerable praise for the way it’s carved a short pathway for accelerated cancer drug approvals. So it’s no surprise that no one is even asking that question.

I’ve added a new category of a biopharma implosion: the self-inflicted pricing scandal. It did in one company on this list, and the same pitfall awaits others. And I’m also adding a line on how the company’s stock did year-to-date. The Dow Jones, offered in context, is up 9% from the beginning of this year.

The nasty surprises outlined below are another reminder of the big gambles every drug developer is engaged in. This isn’t a job for the weak of heart. And too much hubris is even worse.


1
Eli Lilly
Baricitinib goes from blockbuster contender to doghouse tenant in a sudden and devastating fall from grace

Based: Indianapolis, IN
$LLY:+3% YTD
CEO: David Ricks

The scoop: By all accounts, Eli Lilly’s NDA for its blockbuster contender baricitinib looked like a slam dunk. The pharma giant had highlighted solid efficacy data and a safety profile without setting off any alarms. So when the FDA’s rejection was announced in April, the news took everyone by surprise. It took awhile, but Lilly eventually revealed that evidence of blood clots in two of seven studies — Lilly is nothing if not completely thorough in its development work — forced regulators to throw the red flag. The delay on new safety data could now take three or four years to nail down, leaving Lilly looking at a very late comeback attempt after a new round of entries from its rivals. It’s a big decision, and an awful place to be in for new CEO Dave Ricks, who’s been simultaneously rejigging the pipeline. Lilly, though, has a habit of sticking with its late-stage drugs if there’s any chance of success. Lilly’s R&D group ran three failed late-stage studies on their Alzheimer’s drug solanezumab, and they still have clinical work underway on it. The pharma giant went through one of the worst dry spells in the industry, which forced a pledge on a string of new approvals. And recently they got handed a beating in a Phase III head-to-head between its new diabetes drug Trulicity and Novo’s semaglutide. The last thing Ricks needs now is a return to the old, bad days of R&D setbacks.


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IM­brave150: Roche’s reg­u­la­to­ry crew plans a glob­al roll­out of Tecen­triq com­bo for liv­er can­cer as PhI­II scores a hit

Just weeks after Bristol-Myers Squibb defended its failed pivotal study pitting Opdivo against Nexavar in liver cancer, Roche says it’s beat the frontline challenge with a combination of their PD-L1 Tecentriq with Avastin. And now they’re rolling their regulatory teams in the US, Europe and China in search of a new approval — badly needed to boost a trailing franchise effort.
Given their breakthrough and Big Pharma status as well as the use of two approved drugs, FDA approval may well prove to be something of a formality. And the Chinese have been clear that they want new drugs for liver cancer, where lethal disease rates are particularly high.
Researchers at their big biotech sub, Genentech, say that the combo beat Bayer’s Nexavar on both progression-free survival as well as overall survival — the first advance in this field in more than a decade. We won’t get the breakdown in months of life gained, but it’s a big win for Roche, which has lagged far, far behind Keytruda and Opdivo, the dominant PD-1s that have captured the bulk of the checkpoint market so far.
Researchers recruited hepatocellular carcinoma — the most common form of liver cancer — patients for the IMbrave150 study who weren’t eligible for surgery ahead of any systemic treatment of the disease.
Roche has a fairly low bar to beat, with modest survival benefit for Nexavar, approved for this indication 12 years ago. But they also plan to offer a combo therapy that could have significantly less toxicity, offering patients a much easier treatment regimen.
Cowen’s Steven Scala recently sized up the importance of IMbrave150, noting:

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Clay Sie­gall’s $614M wa­ger on tu­ca­tinib pays off with solid­ly pos­i­tive piv­otal da­ta and a date with the FDA

Back at the beginning of 2018, Clay Siegall snagged a cancer drug called tucatinib with a $614 million cash deal to buy Cascadian. It paid off today with a solid set of mid-stage data for HER2 positive breast cancer that will in turn serve as the pivotal win Siegall needs to seek an accelerated approval in the push for a new triplet therapy.

And if all the cards keep falling in its favor, they’ll move from 1 drug on the market to 3 in 2020, which is shaping up as a landmark year as Seattle Genetics prepares for its 23rd anniversary on July 15.
The oral TKI, designed to zero in on HER2 with a bonus for penetrating the blood brain barrier, delivered a 46% hazard ratio — reduction in risk of disease progression or death — when combined with Herceptin and Xeloda compared to the branded combo alone. That was the primary endpoint. And then two key secondaries followed, starting with a 34% reduction in risk of death alone with a p value for overall survival that hit an approval worthy p=0.0048. There was a more dramatic 52% HR among almost half of the patients who had a brain metastasis at the time of the trial, which some of the analysts see as a key to market success.
We’ll have to wait until the San Antonio Breast Cancer Symposium for the breakdown on just how many months of PFS and OS Seattle Genetics is talking about.
While the researchers were after drug resistant third-line cases in the study, where regulators are generous in allowing high levels of toxicity for dying patients, the safety profile is still key here to the drug’s competitive position on the market. By steering clear of EGFR-linked toxicity, the company is looking for a better safety profile. And while the triplet led to a 5.7% drop out rate due to adverse events, compared to 3% for the double, analysts have been scoring this one much better than Nerlynx or Tykerb.

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Med­ical an­i­ma­tion: Mak­ing it eas­i­er for the site and the pa­tient to un­der­stand

Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
Improved accessibility to visualisation
Visualisation is a core component of our ability to understand a concept. Ask 10 people to visualise an apple, and each will come up with a slightly different image, some apples smaller than others, some more round, some with bites taken. Acceptable, you say, we can move on to the next part of the story. Now ask 10 people to visualise how HIV’s capsid protein gets arranged into the hexamers and pentamers that form the viral capsid that holds HIV’s genetic material. This request may pose a challenge even to someone with some virology knowledge, and it is that inability to effectively visualise what is going on that holds us back from fully understanding the rest of the story. So how does medical animation help us to overcome this visualisation challenge?

FDA ap­proval lets Foamix set its maid­en ac­ne ther­a­py on course for US mar­ket launch

Months ago, Foamix leaned on its biggest shareholders — Perceptive Advisors and OrbiMed — to financially grease its wheels, ahead of the FDA decision date for its acne therapy. On Friday, that approval came in — and the topical formulation of the antibiotic minocycline is set for a January launch.

The therapy, Amzeeq (formerly known as FMX101), was approved to treat inflammatory lesions of non-nodular moderate-to-severe acne vulgaris in patients aged 9 and older.

Alice Shaw, Lung Cancer Foundation of America

Top ALK ex­pert and can­cer drug re­searcher Al­ice Shaw bids adieu to acad­e­mia, hel­lo to No­var­tis

Jay Bradner has recruited a marquee oncology drug researcher into the ranks of the Novartis Institutes for BioMedical Research. Alice Shaw is jumping from prestigious posts intertwined through Mass General, Harvard and Dana-Farber to take the lead of NIBR’s translational clinical oncology group.

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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

Last week I had a chance to sit down with Hal Barron at Endpoints’ #UKBIO19 summit to discuss his views on R&D at GSK, a topic that has been central to his life since he took the top research post close to 2 years ago. During the conversation, Barron talked about changing the culture at GSK, a move that involves several new approaches — one of which involves celebrating their setbacks as they shift resources to the most promising programs in the pipeline. Barron also discussed his new alliances in the Bay Area — including his collaboration pact with Lyell, which we covered here — frankly assesses the pluses and minuses of the UK drug development scene, and talks about his plans for making GSK a much more effective drug developer.

This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Christine Bunt, Robert Langer. Verseau

Armed with Langer tech and $50M, Verseau hails new check­point drugs un­leash­ing macrophages against can­cer

The rising popularity of CD47 has propelled the “don’t-eat-me” signal to household name status in the immuno-oncology world: By blocking that protein, the theory goes, one can stop cancer cells from fooling macrophages. But just as PD-(L)1 merely represents the most fruitful of all checkpoints regulating T cells, Verseau Therapeutics is convinced that CD47 is one of many regulators one can modulate to stir up or tame the immune system.

Mi­rati preps its first look at their KRAS G12C con­tender, and they have to clear a high bar for suc­cess

If you’re a big KRAS G12C fan, mark your calendars for October 28 at 4:20 pm EDT.

That’s when Mirati $MRTX will unveil its first peek at the early clinical data available on MRTX849 in presentations at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston.

Mirati has been experiencing the full effect of a rival’s initial success at targeting the G12C pocket found on KRAS, offering the biotech some support on the concept they’re after — and biotech fans a race to the top. Amgen made a big splash with its first positive snapshot on lung cancer, but deflated sky-high expectations as it proved harder to find similar benefits in other types of cancers.

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The FDA will hus­tle up an ex­pe­dit­ed re­view for As­traZeneca’s next shot at a block­buster can­cer drug fran­chise

AstraZeneca paid a hefty price to partner with Daiichi Sankyo on their experimental antibody drug conjugate for HER2 positive breast cancer. And they’ve been rewarded with a fast ride through the FDA, with a straight shot at creating another blockbuster oncology franchise.

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